Many human cancers fail to respond to chemotherapy, and cancers that initially respond frequently acquire drug resistance and relapse. While most of these anti-cancer therapies have been in clinical use for decades, very little is known about the genetic changes that promote drug resistance. As a result, current cancer treatments are applied without a clear understanding of which tumors will respond to which drugs. We propose to use RNA interference (RNAi) technologies in combination with murine stem cell and tumor transplantation systems to investigate the genetic basis for chemotherapeutic resistance. Our aim is to use these tractable mouse models to identify novel cancer drug targets, as well as strategies for tailoring existing cancer therapies to target the vulnerabilities of specific malignancies. We will use both targeted and unbiased approach to identify genes and genetic pathways that dictate the response of B cell lymphomas to well-established genotoxic chemotherapeutics. Initially, we will focus on the BH3-only family of pro-apoptotic mediators to examine the relative role of these proteins in tumor development versus chemotherapeutic response. Subsequently, we will use RNAi screening methodology to examine the role of thousands of cancer-relevant genes in the response to chemotherapy. Finally, we will target established tumor survival pathways to identify genes that, when inactivated, sensitize chemoresistant lymphomas to conventional chemotherapeutics. We expect our studies to identify critical nodes and pathways that ultimately determine the success or failure of a given chemotherapeutic.